Molecular Basis of Transient Outward Potassium Current Downregulation in Human Heart Failure

Kääb, Stefan; Dixon, Jane E.; Duc, Jimmy; Ashen, Dominique; Näbauer, Michael; Beuckelmann, Dirk J.; Steinbeck, Gerhard; McKinnon, David; Tomaselli, Gordon F.

doi:10.1161/01.cir.98.14.1383

Cited by 364 publications

(211 citation statements)

References 60 publications

Supporting

Mentioning

200

Contrasting

Unclassified

Order By: Relevance

“…Indeed, the results presented here suggest that alterations in the functional expression of I to,f and I K1 channels with LVH do not reflect transcriptional or translational downregulation of the subunits encoding these channels, as has been previously suggested. 3,4,29 Rather, the results here suggest that although global transcriptional and translational machineries are acti-vated with LVH, 18 the expression of channel subunits do not increase corresponding to the increase in cell size. Therapeutic strategies aimed at reducing cellular hypertrophy or increasing the functional expression of repolarizing K ϩ channels would, therefore, appear to be promising approaches in the treatment of LVH-associated ventricular arrhythmias.…”

Section: Relationship To Previous Studiesmentioning

confidence: 53%

“…Reduced Kv current densities and action potential prolongation are consistent findings in experimental LVH models [3][4][5][6][7][8][9]11 and in failing human hearts. 10,29 The analyses completed here, however, revealed that cellular hypertrophy (increased C m ) is the main factor in determining reductions in I to,f and I K1 densities, because the mean amplitudes of these currents in TAC and sham LV cells were not significantly different. In contrast, mean I K,slow and I ss amplitudes were altered in TAC LV myocytes, suggesting that functional I K,slow and I ss channel expression is modulated with LVH.…”

Section: Marionneau Et Al Mechanisms Underlying K ؉ Current Remodelinmentioning

confidence: 57%

“…Several previous studies have described reductions in K ϩ current densities with LVH or heart failure. [5][6][7][8][9][10][11]29 Most of these studies reported 30% to 50% decreases in K ϩ current densities, with cell membrane capacitances increased by approximately the same percentage. Although not reported, it seems likely that K ϩ current amplitudes were also largely unaffected in these previous studies and that increased cell size was the primary determinant of the reductions in K ϩ current densities.…”

Section: Relationship To Previous Studiesmentioning

confidence: 99%

See 2 more Smart Citations

Left Ventricular Hypertrophy

Ebert¹

2005

Easy ECG

View full text Add to dashboard Cite

Abstract-Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K ϩ channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT c intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C m ) was higher, and Key Words: hypertrophy Ⅲ arrhythmia Ⅲ heart failure L eft ventricular hypertrophy (LVH) is an adaptive response of the myocardium to an increase in load. 1 LVH is seen in various disease states including hypertension and myocardial infarction, as well as in valvular and congenital heart diseases. 1 LVH is also observed in physiological states following rigorous, prolonged exercise. 2 Although physiological LVH does not confer increased morbidity and mortality, pathological LVH is consistently associated with prolongation of ventricular action potentials and alterations in the dispersion of repolarization, both of which result in electric instability and increase the propensity to develop lifethreatening arrhythmias. 3 Several lines of evidence suggest that these electric changes reflect, at least in part, alterations in the functioning of the K ϩ channels that underlie ventricular action potential repolarization. 3,4 Various experimental models of LVH, 5-7 including pressure overload-induced LVH, 8,9 have been developed to explore the mechanisms underlying K ϩ current remodeling.Although several studies have examined regional differences in remodeling, 8 -11 few have probed the underlying molecular and cellular mechanisms. In the studies here, a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC), was exploited to quantify the effects of LVH on repolarizing K ϩ currents in LV myocytes and to delineate the mechanisms underlying K ϩ current remodeling. These experiments revealed that APDs were prolonged in TAC LV myocytes and that QT c intervals were increased in TAC mice. Mean whole-cell membrane capacitance (C m ) was increased significantly, and the densities of voltage-gated K ϩ (Kv) and inwardly rectifying K ϩ (Kir) currents were reduced in TAC LV myocytes. Further electrophysiological, molecular, and biochemical analyses revealed marked regional differences in the effects of LVH and that distinct cellular and molecular mechanisms contribute to the functional remodeling of repolarizing Kv and Kir currents.

show abstract

Section: Relationship To Previous Studiesmentioning

confidence: 53%

Section: Marionneau Et Al Mechanisms Underlying K ؉ Current Remodelinmentioning

confidence: 57%

Section: Relationship To Previous Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Left Ventricular Hypertrophy

Ebert¹

2005

Easy ECG

View full text Add to dashboard Cite

show abstract

“…Western blot analyses of atrial and ventricular membrane proteins confirmed the presence of Kcna2 at 75 kDa in adult rat heart membranes 8. Furthermore, Kcna2 has also been observed in human ventricular tissue 5. Herein, Kcna2 RNA and protein expression was detected (Figure S2).…”

Section: Discussionmentioning

confidence: 67%

“…However, the molecular mechanisms underlying arrhythmias are still unknown 3. Delayed rectifier potassium channels are important for controlling the repolarization of several ion species in the heart, and decreases in the delayed rectifier potassium current (I K ) in heart failure results in action potential (AP) prolongation, which is an important contributor to the development of ventricular arrhythmias 4, 5, 6. Kcna2, also known as Kv1.2, which is a subunit of the voltage‐gated shaker channel family, is one of the dominant ion channels in cardiac muscle and encodes I K 7, 8.…”

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

Long

Wang

Gao

et al. 2017

JAHA

View full text Add to dashboard Cite

BackgroundCongestive heart failure (CHF) is a common cardiovascular disease that is often accompanied by ventricular arrhythmias. The decrease of the slow component of the delayed rectifier potassium current (IK s) in CHF leads to action potential (AP) prolongation, and the IK s is an important contributor to the development of ventricular arrhythmias. However, the molecular mechanisms underlying ventricular arrhythmias are still unknown.Methods and ResultsKcna2 and Kcna2 antisense RNA (Kcna2 AS) transcript expression was measured in rat cardiac tissues using quantitative real‐time reverse transcription–polymerase chain reaction and Western blotting. There was a 43% reduction in Kcna2 mRNA in the left ventricular myocardium of rats with CHF. Kcna2 knockdown in the heart decreased the IKs and prolonged APs in cardiomyocytes, consistent with the changes observed in heart failure. Conversely, Kcna2 overexpression in the heart significantly attenuated the CHF‐induced decreases in the IKs, AP prolongation, and ventricular arrhythmias. Kcna2 AS was upregulated ≈1.7‐fold in rats with CHF and with phenylephrine‐induced cardiomyocyte hypertrophy. Kcna2 AS inhibition increased the CHF‐induced downregulation of Kcna2. Consequently, Kcna2 AS mitigated the decrease in the IKs and the prolongation of APs in vivo and in vitro and reduced ventricular arrhythmias, as detected using electrocardiography.ConclusionsVentricular Kcna2 AS expression increases in rats with CHF and contributes to reduced IK s, prolonged APs, and the occurrence of ventricular arrhythmias by silencing Kcna2. Thus, Kcna2 AS may be a new target for the prevention and treatment of ventricular arrhythmias in patients with CHF.

show abstract

Repolarization Reserve and Proarrhythmic Risk

Varró

2009

Novel Therapeutic Targets for Antiarrhythmic Drugs

View full text Add to dashboard Cite

Molecular Basis of Transient Outward Potassium Current Downregulation in Human Heart Failure

Abstract: These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac Ito in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.

Cited by 364 publications

References 60 publications

Left Ventricular Hypertrophy

Left Ventricular Hypertrophy

Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

Repolarization Reserve and Proarrhythmic Risk

Contact Info

Product

Resources

About